5,6-Diaryl-1,2,4-triazines as topically-active anti-inflammatory agents

ABSTRACT

A method of treating inflammation which utilizes topically-active 5,6-diaryl-1,2,4-triazines having the formula,   &lt;IMAGE&gt;   wherein R is hydrogen or -(X)nR1, in which X is either O or S, n is an integer which is either 0 or 1, and R1 is C1-C8 alkyl, C7-C8 aralkyl, C3-C8 cycloalkyl, or C4-C8 (cycloalkyl)alkyl; and R2 and R3 independently are halo, C1-C3 alkyl, C1-C3 alkoxy, or di(C1-C3 alkyl)amino, with the proviso that at least one of R2 and R3 is halo or C1-C3 alkyl; and the pharmaceutically-acceptable acid addition salts of basic members thereof.

BACKGROUND OF THE INVENTION

This invention relates to anti-inflammatory 5,6-diaryl-1,2,4-triazines. More particularly, this invention relates to a method of treating inflammation with topically-active anti-inflammatory 5,6-diaryl-1,2,4-triazines.

Inflammation is an essentially protective and normal response to injury, although the etiology and pathogenesis of many inflammatory conditions remain obscure. In general, anti-inflammatory agents are employed primarily to relieve the symptoms of inflammation. In such symptomatic therapy, topically-applied anti-inflammatory agents present special problems. Inflammatory conditions calling for the topical application of an anti-inflammatory agent are almost exclusively treated with steroids. Topically-applied steroids, however, may carry considerable systemic toxicity. Thus, the need continues for safer, better tolerated topically-active anti-inflammatory agents.

SUMMARY OF THE INVENTION

In accordance with the present invention, a method of treating inflammation in a warm-blooded mammal is provided which comprises topically administering to such mammal an effective amount of a compound of the formula, ##STR2## wherein R is hydrogen or --(X)_(n) R₁, in which X is either O or S, n is an integer which is either 0 or 1, and R₁ is C₁ -C₈ alkyl, C₇ -C₈ aralkyl, C₃ -C₈ cycloalkyl, or C₄ -C₈ (cycloalkyl)alkyl; and R₂ and R₃ independently are halo, C₁ -C₃ alkyl, C₁ -C₃ alkoxy, or di(C₁ -C₃ alkyl)amino, with the proviso that at least one of R₂ and R₃ is halo or C₁ -C₃ alkyl; and the pharmaceutically-acceptable acid addition salts of basic members thereof.

As used herein, "an effective amount" means an amount sufficient to at least in part ameliorate the inflammatory condition under treatment. The relief afforded thereby can be observed as a reduction in the intersity of the inflammation, a reduction in the time period during which the inflammatory condition persists, or both, and in instances where pretreatment is possible, a delay in the appearance of the inflammatory condition also can be observed.

The compounds employed in the present invention are especially useful as topically-active anti-inflammatory agents in warm-blooded mammals, such as guinea pigs, mice, rats, dogs, monkeys, humans, and the like.

DETAILED DESCRIPTION OF THE INVENTION

The term "C₁ -C₈ alkyl" includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 1-methylbutyl, 1-ethylpropyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, hexyl, isohexyl, 2-ethylbutyl, 1-ethyl-1-methylpropyl, heptyl, 2-ethyl-1-methylbutyl, 2,4-dimethylpentyl, octyl, 2-ethylhexyl, 1,1-diethylbutyl, and the like.

The term "C₇ -C₈ aralkyl" includes benzyl, 2-phenylethyl, p-methylbenzyl, m-methylbenzyl, o-methylbenzyl, and the like.

The term "C₃ -C₈ cycloalkyl" includes cyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-ethyl-3-methylcyclobutyl, cyclopentyl, 3-isopropylcyclopentyl, cyclohexyl, 1-methylcyclohexyl, 2,5-dimethylcyclohexyl, cycloheptyl, 3-methylcycloheptyl, cyclooctyl, and the like.

The term "C₄ -C₈ (cycloalkyl)alkyl" includes cyclopropylmethyl, 3-cyclopropyl-2-methylbutyl, 3-(2-methylcyclobutyl)propyl, 2-cyclopentylethyl, 4-methylcyclohexylmethyl, cycloheptylmethyl, and the like.

The term "C₁ -C₃ alkoxy" includes methoxy, ethoxy, propoxy, and isopropoxy. The term "C₁ -C₃ alkyl" includes methyl, ethyl, propyl, and isopropyl. The term "halo" includes fluoro, chloro, bromo, and iodo.

Illustrative of the triazine compounds which are employed in the present invention are the following:

5,6-bis(4-fluorophenyl)-1,2,4-triazine,

5,6-bis(4-fluorophenyl)-3-methyl-1,2,4-triazine,

5,6-bis(4-fluorophenyl)-3-methoxy-1,2,4-triazine,

5,6-bis(4-fluorophenyl)-3-methylthio-1,2,4-triazine,

5,6-bis(4-methylphenyl)-1,2,4-triazine,

3-methyl-5,6-bis(4-methylphenyl)-1,2,4-triazine,

3-methoxy-5,6-bis(4-methylphenyl)-1,2,4-triazine,

5,6-bis(4-methylphenyl)-3-methylthio-1,2,4-triazine,

6-(4-bromophenyl)-5-(4-iodophenyl)-1,2,4-triazine,

5-(4-ethylphenyl)-6-(4-propylphenyl)-1,2,4-triazine,

6-(4-fluorophenyl)-5-(4-methylphenyl)-1,2,4-triazine,

5-(4-methoxyphenyl)-6-(4-methylphenyl)-1,2,4-triazine,

5-(4-diethylaminophenyl)-6-(4-fluorophenyl)-1,2,4-triazine,

5-(4-fluorophenyl)-3-methyl-6-(4-methylphenyl)-1,2,4-triazine,

6-(4-fluorophenyl)-3-methoxy-5-(4-methylphenyl)-1,2,4-triazine,

5-(4-methoxyphenyl)-6-(4-methylphenyl)-3-methylthio-1,2,4-triazine,

6-(4-dimethylaminophenyl)-3-methyl-5-(4-methylphenyl)-1,2,4-triazine,

5-(4-dimethylaminophenyl)-6-(4-fluorophenyl)-3-methoxy-1,2,4-triazine,

5-(4-chlorophenyl)-6-(4-fluorophenyl)-3-methyl-1,2,4-triazine,

6-(4-chlorophenyl)-3-neopentyloxy-5-(4-propylphenyl)-1,2,4-triazine,

3-(2,3-dimethylpentylthio)-5-(4-ethylphenyl)-6-(4-isopropoxyphenyl)-1,2,4-triazine,

3-benzyl-5-(4-methylphenyl)-6-(4-propylphenyl)-1,2,4-triazine,

6-(4-dimethylaminophenyl)-5-(4-isopropylphenyl)-3-(p-methylbenzyloxy)-1,2,4-triazine,

3-cyclobutyl-5-(4-ethoxyphenyl)-6-(4-ethylphenyl)-1,2,4-triazine,

3-cyclopropyloxy-6-(4-dipropylaminophenyl)-5-(4-fluorophenyl)-1,2,4-triazine,

5,6-bis(4-fluorophenyl)-3-(3-methylcyclohexylthio)-1,2,4-triazine,

5,6-bis(4-ethylphenyl)-3-[2-(3-methylcyclopentyl)-ethyl]-1,2,4-triazine,

3-cyclobutylmethoxy-5-(4-diethylaminophenyl)-6-(4-methylphenyl)-1,2,4-triazine,

3-cyclopropylmethylthio-6-(4-fluorophenyl)-5-(4-propylphenyl)-1,2,4-triazine, and the like,

and the pharmaceutically-acceptable acid addition salts of the basic triazines.

The compounds employed in the method of the present invention are prepared by a variety of methods known to those having ordinary skill in the art. Starting materials and intermediates also are prepared by known methods. The preparation of 5,6-diaryl-1,2,4-triazines is described generally by J. G. Erickson in "The 1,2,3- and 1,2,4-Triazines, Tetrazines and Pentazines," The Chemistry of Heterocyclic Compounds, Vol. 10, Interscience Publishers, Inc., New York, N.Y., 1956, Chapter II, pp. 44-84. The 5,6-diaryl-1,2,4-triazines which are unsubstituted in the 3-position can be prepared by the catalytic reduction of the corresponding 3-chlorotriazines.

The specific procedure employed to prepare a given 3-substituted-5,6-diaryl-1,2,4-triazine in part is dependent upon the substituent in the 3-position. For example, 3-alkyl-, 3-aralkyl-, 3-cycloalkyl-, and 3-(cycloalkyl)alkyl-5,6-diaryl-1,2,4-triazines can be prepared directly by the cyclization of acylhydrazones of α-diketones by ammonium acetate in hot acetic acid under controlled conditions; see, e.g., C. M. Atkinson and H. D. Cossey, J. Chem. Soc., 1962, 1805 [Chem. Abstr., 57:4662i (1962)]. Such triazines also can be prepared from 3-chloro-5,6-diaryl-1,2,4-triazines by the procedure of E. C. Taylor and S. F. Martin [J. Amer. Chem. Soc., 94, 2874 (1972)] which involves the nucleophilic displacement of chlorine by a Wittig reagent which may be generated in situ from an alkyl-, aralkyl-, cycloalkyl-, or (cycloalkyl)alkyltriarylphosphonium halide.

3-Chloro-5,6-diaryl-1,2,4-triazines also can be employed to prepare the 3-alkoxy, 3-aralkoxy-, 3-cycloalkoxy-, 3-(cycloalkyl)alkoxy-, 3-alkylthio-, 3-aralkylthio-, 3-cycloalkylthio-, and 3-(cycloalkyl)alkylthio-5,6-diaryl-1,2,4-triazines via the nucleophilic displacement of chlorine by the appropriate alcohol or thiol. The 3-alkylthio-, 3-aralkylthio-, 3-cycloalkylthio-, and 3-(cycloalkyl)alkylthio- compounds can be converted to the 3-alkoxy-, 3-aralkoxy-, 3-cycloalkoxy-, and 3-(cycloalkyl)alkoxy-5,6-diaryl-1,2,4-triazines, again via nucleophilic displacement by the appropriate alcohol. The 3-alkylthio-, 3-aralkylthio-, 3-cycloalkylthio, and 3-(cycloalkyl)alkylthiotriazines also can be prepared by treating the appropriate 3-mercapto-5,6-diaryl-1,2,4-triazine with the appropriate hydrocarbyl halide in the presence of base.

3-Chloro-5,6-diaryl-1,2,4-triazines are readily obtained by treating the appropriate 3-hydroxytriazine with phosphorus oxychloride. 3-Hydroxy- and 3-mercapto-5,6-diaryl-1,2,4-triazines in turn can be prepared by condensing an appropriate benzil with semicarbazide or thiosemicarbazide, respectively.

The required benzils are prepared by the oxidation of the corresponding benzoins with copper sulfate in pyridine; see H. T. Clarke and E. E. Driger, Org. Synthesis, Coll. Vol. I, 87 (1941). The benzoins are prepared by the condensation of aromatic aldehydes with cyanide ion; see W. S. Ide and J. S. Buck, Org. Reactions, 4, 269 (1948).

Another approach to the compounds employed in the present invention involves the use of benzils having substituents which can be displaced to give the desired R₂ or R₃ substituent. For example, the halogen on the phenyl ring at the 5-position in 5-(4-halophenyl)-6-aryl-1,2,4-triazines can be displaced with an alcohol or a dialkylamine to give the corresponding 5-(4-alkoxyphenyl)- or 5-(4-dialkylaminophenyl)- compound, respectively.

The use of two different aromatic aldehydes in the benzoin synthesis leads to unsymmetrical benzils. That is, in a benzil of the formula, ##STR3## wherein R₂ and R₃ are as described hereinbefore, R₂ and R₃ are different. The use of an unsymmetrical benzil may result in the preparation of a mixture of triazine isomers. For example, the condensation of 4-dimethylamino-4'-methoxybenzil with thiosemicarbazide gives a mixture of 5-(4-dimethylaminophenyl)-6-(4-methoxyphenyl)-1,2,4-triazine-3-thiol and 6-(4-dimethylaminophenyl)-5-(4-methoxyphenyl)-1,2,4-triazine-3-thiol.

It will be recognized by those skilled in the art that mixtures of triazine isomers are separable by known methods, such as fractional crystallization and chromatography. The isomer separation may be effected upon intermediate mixtures or delayed until the final product stage.

Certain of the 5,6-diaryl-1,2,4-triazines employed herein are sufficiently basic to form acid addition salts, especially when the triazine contains a dialkylamino group on a phenyl ring. "Pharmaceutically-acceptable" acid addition salts are well known to those skilled in the art and in general are formed by reacting in a mutual solvent a stoichiometric amount of a suitable acid with a basic triazine. Such salts should not be substantially more toxic to warm-blooded animals than the triazines. While the choice of a salt-forming acid is not critical, in some instances a particular acid may result in a salt having special advantages, such as ready solubility, ease of crystallization, and the like. Representative and suitable acids include, among others, the following: hydrochloric, hydrobromic, hydriodic, sulfuric, nitric, phosphoric, methanesulfonic, p-toluenesulfonic, and the like.

As stated hereinbefore, the present invention provides a method of treating inflammation in a warm-blooded mammal which comprises topically administering to such mammal an effective amount of a compound of the formula, ##STR4## wherein R, R₂, and R₃ have the meanings previously defined; and the pharmaceutically-acceptable acid addition salts of basic members thereof.

The preferred compounds are those wherein at least one of R₂ and R₃ in the above-defined formula is fluoro or methyl. More preferably, R₂ and R₃ will be the same, and most preferably are fluoro or methyl. With respect to the substituent in the 3-position, the preferred groups are C₁ -C₈ alkyl (R is --(X)_(n) R₁, n is 0, and R₁ is C₁ -C₈ alkyl), C₁ -C₈ alkoxy (R is --(X)_(n) R₁, n is 1, X is 0, and R₁ is C₁ -C₈ alkyl), and C₁ -C₈ alkylthio (R is --(X)_(n) R₁, n is 1, X is S, and R₁ is C₁ -C₈ alkyl). More preferably, the 3-substituent is C₁ -C₈ alkyl or C₁ -C₈ alkoxy. More preferably, the 3-substituent is C₁ -C₃ alkyl or C₁ -C₃ alkoxy. Illustrative of the compounds which can be employed in the method of the present invention, as well as such preferred, more preferred, and most preferred compounds, are the triazines listed hereinabove.

A modification of the method of Winder was used to measure the anti-inflammatory activities of the compounds employed in the method of the present invention; see C. V. Winder, et. al., Arch. Int. Pharmacodyn., 116, 261 (1958). Albino guinea pigs of either sex, weighing 225-300 grams, were shaved on the back and chemically depilated (Nair Lotion Hair Remover, Carter Products, N.Y., N.Y.) 18-20 hours before exposure to ultraviolet light. The animals, in groups of four and bearing identifying ear tags, were treated by applying to an area of skin of about 12 cm.² a solution of test compound dissolved in 0.1 cc. of ethanol. The control treatment consisted of administering only the drug vehicle, ethanol, to a group of four animals. Groups of four animals each were given different treatment levels of test compound to obtain dose responses. Random order and blind administration of the test compounds were employed; drug identification was not made until after all animals were graded. Immediately prior to drug application, the animals were exposed in groups of four to a high-intensity ultraviolet light for a measured period of time (usually 4-7 seconds). The ultraviolet light source, a Hanovia Lamp (Kroymayer-Model 10), was placed in contact with the skin of the animal's back. A gummed notebook paper reinforcement was affixed to the lamp lens to provide an unexposed area of contrast for grading the erythema. Beginning one hour after exposure and thereafter at half-hour intervals for another 11/2 hours, the degree of resulting erythema was graded by an arbiturary scoring system based upon the degree of contrast and redness formed. Anti-inflammatory agents delay the development of the erythema and usually have their greatest effect at the initial grading periods. The scores were, therefore, weighted by factors of 4, 3, 2, and 1 at the 1.0, 1.5, 2.0, and 2.5 hour scoring times, respectively. The erythema was graded as follows:

    ______________________________________                                         Erythema Scoring System                                                        Score         Appearance of Exposed Area                                       ______________________________________                                         0             No redness and no contrast                                       1             Slight redness with a faint                                                    reinforcement outline                                            2             Slight to moderate redness                                                     with a distinct outline                                          3             Marked redness with a distinct                                                 circular outline                                                 ______________________________________                                    

Total scores from each treatment group of four guinea pigs were compared to the control treatment, and the percent inhibition was calculated as follows: ##EQU1##

A dose-response graph is obtained by plotting dose versus the average percent inhibition of each treatment group of four guinea pigs. The dose (ED₅₀) in micrograms per 12 cm.² (mcg./12 cm.²) which produces a 50% inhibition of the erythemic response for the particular compound tested is obtained by extrapolation. In general, the 5,6-diaryl-1,2,4-triazines employed in the present invention result in at least about 20 percent inhibition at dose levels below about 10³ mcg./12cm.² For example, 3-methoxy-5,6-bis(4-methylphenyl)-1,2,4-triazine has an ED₅₀ of 20.5 mcg./12cm.², and 5,6-bis(4-fluorophenyl)-3-methylthio-1,2,4-triazine has an ED₅₀ of 13 mcg./12cm.²

The toxicities of representative compounds employed in the method of the present invention, determined as the dose (LD₅₀) in milligrams per kilogram (mg./kg.) of animal body weight which is lethal to 50 percent of mice treated orally, typically are greater than about 1000 mg./kg., and in some cases are greater than about 1500 mg./kg.

The method of the present invention can be used in the treatment of a variety of inflammatory conditions which are susceptible to treatment with topically-active anti-inflammatory agents. Such inflammatory conditions include, among others, atropic dermatitis, contact dermatitis, nummular eczema, lichen simplex, psoriasis, chronic dermatoses, and ultraviolet-induced erythema.

In the practice of this invention, one (or more) of the anti-inflammatory triazines is topically administered to a warm-blooded mammal in an effective amount. In general, such amount should be sufficient to provide at least about 1 mcg. of triazine per 12 cm.² of skin surface area (1 mcg./12cm.²). Because of the relatively low order of toxicity of such triazines, the maximum level of application basically is limited only by the esthetics of the mode of administration. As a practical matter, however, such triazines normally need not be administered at levels much above about 10³ mcg./12 cm.², although levels of about 10⁵ mcg./12 cm.² or higher can be employed, if desired.

The specific dose level for any given triazine depends upon a number of factors, such as the nature and severity of the inflammatory condition, the potency of the triazine, the concentration of the triazine in the topically applied composition or medicament, the nature of the composition or medicament vehicle, the presence of absorption adjuvants, and the lipid solubility of the triazine. For a discussion of factors involved in the topical absorption of drugs, see "Remington's Pharmaceutical Sciences," 14th Ed., Mack Publishing Company, Easton, Pennsylvania, 1970, pp. 741-746. As already indicated, dose levels can range from about 1 mcg./12 cm.² to about 10⁵ mcg./12 cm.² skin surface area, preferably from about 1 mcg./12 cm.² to about 10³ mcg./12 cm.² The anti-inflammatory triazine can be administered one or more times daily, with multiple applications being preferred. Such multiple applications typically will range from about two to about four per day.

The topical administration of the anti-inflammatory triazines can be made according to any of the well known prior art procedures, which include inunction, spraying, painting, and the like, as well as dispensing from conventional surgical gauze dispensers, collodion, absorbable gelatin film, petrolatum gauze, zinc gelatin, and the like. Thus, such administration can utilize aerosols, creams, emulsions, lotions, oils, ointments, solutions, and the like. In each case, the compounds to be employed in accordance with the present invention are utilized in combination with one or more adjuvants suited to the particular mode of application. For example, ointments and solutions for topical administration can be formulated with any of a number of pharmaceutically-acceptable carriers, including ethanol, animal and vegetable oils, mixtures of waxes, solid and liquid hydrocarbons, glycols, and the like.

Such terms as "adjuvants" and "pharmaceutically-acceptable carriers" are meant to include cosmetic carriers and bases, such as ethanol and other organic solvents; oil-in-water and water-in-oil emulsions, employed as both creams and lotions, anhydrous systems, comprising, for example, vegetable waxes, vegetable oils, paraffin waxes, paraffin oils, and any combination thereof; and hydrous gels, utilizing gelatin, xanthate gums, synthetic resins, and the like as gelling agents.

The concentration of the anti-inflammatory triazine in the final topical preparation is not critical. In general, such concentration can range from about 0.001 percent to about 50 percent (w/w or w/v), or higher. Preferably, such concentration will be in the range of from about 0.01 percent to about 10 percent.

If desired, the final topical preparation can contain one or more components having pharmacological or other activities separate and distinct from the activity of the triazines. Examples of such components include, among others, insect repellants, topical anesthetics, bacteriostats, fungicides, astringents, sunscreen agents, and the like. Alternatively, the triazines employed in the method of the present invention can be incorporated into existing or known compositions, such as antiseptics, topical anesthetics, protectives and adsorbents, demulcents, emollients, astringents, antiphlogistics, antipruritics, and the like, the preparation and use of which are well known to those having ordinary skill in the art; see, for example, "Remington's Pharmaceutical Sciences," supra, pp. 763-786. Of particular preference is the incorporation of such triazines into cosmetic formulations, such as sunscreen, suntan, and sunburn preparations.

In accordance with well known procedures, the final topical preparation can contain, in addition to components already described, solvents, preservatives, emulsifiers, surface active agents, perfumes, water, and the like.

By way of example only, some representative triazine-containing formulations follow. Unless otherwise indicated, all percentages are w/w.

    ______________________________________                                         Ointment                Percent                                                ______________________________________                                         Triazine                10                                                     Polyethylene glycol 400 55                                                      (N.F.)                                                                        Polyethylene glycol 4000                                                                               35                                                      (U.S.P)                                                                       Perfume                 q.s.                                                   Lotion                  Percent                                                ______________________________________                                         Triazine                1                                                      Ethyl alcohol (denatured)                                                                              69                                                     Oleyl alcohol           10                                                     Water                   20                                                     Perfume                 q.s.                                                   Triazine                1                                                      L-43 Silicone.sup.a     5                                                      Ethyl alcohol           94                                                     Perfume                 q.s.                                                   Oil                     Percent                                                ______________________________________                                         Triazine                2                                                      Castor oil              90                                                     Butylated hydroxytoluene                                                                               0.02                                                   Ethanol                 to 100                                                 Perfume                 q.s.                                                   Anesthetic ointment     Percent                                                ______________________________________                                         Benzocaine              5                                                      Triazine                3                                                      Methylparaben           0.025                                                  Propylparaben           0.015                                                  Sodium lauryl sulfate   1                                                      Propylene glycol        11                                                     Stearyl alcohol         24                                                     White petrolatum        24                                                     Perfume                 q.s.                                                   Water                   to 100                                                 Protective ointment     Percent                                                ______________________________________                                         Zinc oxide              20                                                     Triazine                3                                                      Mineral oil             15                                                     White wax               3.1                                                    White Petrolatum        58.9                                                   Perfume                 q.s.                                                   Sunscreen/Insect                                                               repellent cream         Percent                                                ______________________________________                                         Triazine                2                                                      Castor oil              10                                                     N,N-Diethyltoluamide    15                                                     Ethyl p-dimethylaminobenzoate                                                                          2                                                      Glyceryl monostearate   10                                                     Stearic acid            2                                                      Ethoxylate lanolin alcohol                                                                             2                                                      Butylated hydroxytoluene                                                                               0.02                                                   Cellosize QP 15,000.sup.a                                                                              0.25                                                   Methylparaben           0.15                                                   Triethanolamine         1                                                      Perfume oil             0.5 v/w                                                Water                   to 100                                                 sunscreen oil           Percent                                                ______________________________________                                         Triazine                1                                                      Octyl p-dimethylaminobenzoate                                                                          1                                                      Silicone fluid L-45 (100 cS)                                                                           10                                                     Isopropyl palmitate     88                                                     Aerosol sunscreen oil   Percent                                                ______________________________________                                         Triazine                1                                                      Ethyl p-dimethylaminobenzoate                                                                          5                                                      Isopropyl myristate     25                                                     L-43 Silicone.sup.a     5                                                      Perfume oil             1.25                                                   Lanolin oil             2.5                                                    Menthol Racemic U.S.P.  0.25                                                   Absolute alcohol        60                                                     Fill                    Percent                                                ______________________________________                                         Concentrate             20                                                     Propellant 11/12 (75:25).sup.b                                                                         80                                                     Palliative preparation                                                         for sunburn             Percent                                                ______________________________________                                         Triazine                5                                                      Colloidal calamine      10                                                     Triethanolamine stearate                                                                               4.8                                                    Liquid paraffin         10                                                     Water                   70.2                                                   Antiseptic              q.s.                                                   Suntan preparation      Percent                                                ______________________________________                                         Triazine                1.7                                                    Dihydroxyacetone        4                                                      Ethanol (95%)           28                                                     Methylp-hydroxybenzoate 1                                                      Sorbitol syrup (70%)    3                                                      Boric acid powder       1                                                      Allantoin               0.3                                                    Distilled water         59                                                     Perfume                 2                                                      ______________________________________                                          .sup.a Union carbide corp., New York                                           .sup.b Trichlorofluoromethane/dichlorodifluoromethane                    

The following examples further illustrate the preparations of the compounds employed in the method of the present invention.

EXAMPLE 1 Preparation of 5,6-Bis(4-fluorophenyl)-3-methylthio-1,2,4-triazine

A. 5,6-Bis(4-fluorophenyl)-3-mercapto-1,2,4-triazine

A solution of 80 g. of 4,4'-difluorobenzil in 400 ml. of ethanol was heated to reflux. Water then was added to the point of incipient turbidity, followed by the addition of 80 g. of thiosemicarbazide and 96 g. of sodium acetate. The reaction mixture was heated at reflux for one hour. Water again was added to the reaction mixture to the point of incipient turbidity. Sodium hydroxide, 80 g., then was added gradually to the reaction mixture, which then was heated at reflux for one hour. The reaction mixture was poured into a 3-fold volume of ice water and aqueous hydrochloric acid was added until the mixture was strongly acidic. The solid which precipitated was isolated by filtration and recrystallized from acetic acid to give 57.5 g. of 5,6-bis(4-fluorophenyl)-3-mercapto-1,2,4-triazine, m.p. about 180°-182° C.

Analysis: C₁₅ H₉ F₂ N₃ S;

Calc: C, 59.79; H, 3.01 N, 13.95;

Found: C, 59.96; H, 3.12; N, 14.05.

B. 5,6-Bis(4-fluorophenyl)-3-methylthio-1,2,4-triazine

To a solution of 26.5 g. of 5,6-bis(4-fluorophenyl)-3-mercapto-1,2,4-triazine and 4 g. of sodium hydroxide in 300 ml. of ethanol was added 24.2 g. of methyl iodide. The mixture was agitated at ambient temperature. The precipitate which formed was isolated by filtration and recrystallized from ethanol, giving 14 g. of 5,6-bis(4-fluorophenyl)-3-methylthio-1,2,4-triazine, m.p. about 134°-136° C.

Analysis: C₁₆ H₁₁ F₂ N₃ S;

Calc: C, 60.94; H, 3.52; F, 12.05; N, 13.33;

Found: C, 60.72; H, 3.48; F, 11.92; N, 13.04.

EXAMPLE 2 Preparation of 5-(4-Dimethylaminophenyl)-6-(4-fluorophenyl)-3-methylthio-1,2,4-triazine

A. 5-(4-Dimethylaminophenyl)-6-(4-fluorophenyl)-3-Mercapto-1,2,4-triazine

To a solution of 8.1 g. of 4-dimethylamino-4'-fluorobenzil in 65 ml. of acetic acid was added 3.3 g. of thiosemicarbazide. The reaction mixture then was heated at reflux for three hours. The solid which precipitated was isolated by filtration, washed successively with ethanol and water, and dried, giving 4.3 g. of 5-(4-dimethylaminophenyl)-6-(4-fluorophenyl)-3-mercapto-1,2,4-triazine, m.p. about 262°-264° C.

Analysis: C₁₇ H₁₅ FN₄ S;

Calc: C, 62.57; H, 4.63; F, 5.82; N, 17.17;

Found: C, 62.83; H, 4.73; F, 5.70; N, 17.29.

B. 5-(4-Dimethylaminophenyl)-6-(4-fluorophenyl)-3-methylthio-1,2,4-triazine

To a solution of 0.48 g. of sodium hydroxide in 100 ml. of ethanol was added 4 g. of 5-(4-dimethylaminophenyl)-6-(4-fluorophenyl)-3-mercapto-1,2,4-triazine. To the resulting solution was added, with agitation, 2.1 g. of methyl iodide. The precipitate which formed was isolated by filtration and recrystallized from ethanol to give 2.9 g. of 5-(4-dimethylaminophenyl)-6-(4-fluorophenyl)-3-methylthio-1,2,4-triazine, m.p. about 144°-146° C.

Analysis: C₁₈ H₁₇ FN₄ S;

Calc: C, 63.51; H, 5.03; N, 16.46; S, 9.42;

Found: C, 63.22; H, 5.30; N, 16.24; S, 9.23.

EXAMPLE 3 Preparation of 5,6-Bis(4-methylphenyl)-3-methylthio-1,2,4-triazine

A. 3-Mercapto-5,6-bis(4-methylphenyl)-1,2,4-triazine

To a solution of 85 g. of 4,4'-dimethylbenzil in 360 ml. of acetic acid heated to about 80°-100° C. was added 35.5 g. of thiosemicarbazide, portionwise, over a 10-minute period. The reaction mixture was heated at reflux for two hours. The reaction mixture was cooled and diluted with 500 ml. of water. The solid which precipitated was isolated by filtration, washed with water, and recrystallized from ethanol to give 22 g. of 3-mercapto-5,6-bis(4-methylphenyl)-1,2,4-triazine, m.p. about 220°-223° C.

Analysis: C₁₇ H₁₅ N₃ S;

Calc: C, 69.60; H, 5.15; N, 14.32;

Found: C, 69.32; H, 5.36; N, 14.60.

B. 5,6-Bis(4-methylphenyl)-3-methylthio-1,2,4-triazine

To a solution of 24 g. sodium hydroxide in about one liter of ethanol was added 146.5 g. of 3-mercapto-5,6-bis(4-methylphenyl)-1,2,4-triazine. To the resulting solution was added 88.2 g. of methyl iodide. The reaction mixture was agitated overnight at ambient temperature. The solid which precipitated was isolated by filtration and washed with ethanol; the solid was recrystallized from ethanol to give 101.1 g. of 5,6-bis(4-methylphenyl)-3-methylthio-1,2,4-triazine, m.p. about 170°-172° C.

Analysis: C₁₈ H₁₇ N₃ S;

Calc: C, 70.33; H, 5.57; N, 13.67;

Found: C, 70.25; H, 5.78; N, 13.72.

EXAMPLE 4 Preparation of 3-Methoxy-5,6-bis(4-methylphenyl)-1,2,4-triazine

A solution of sodium methoxide in methanol was prepared by reacting 5 g. of sodium with 350 ml. of methanol. To such solution was added 61.4 g. of 5,6-bis(4-methylphenyl)-3-methylthio-1,2,4-triazine. The reaction mixture was heated at reflux for six hours, then was allowed to stir overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water. The insoluble solid was isolated by filtration and recrystallized from ethanol to give 3-methoxy-5,6-bis-(4-methylphenyl)-1,2,4-triazine, m.p. about 125°-128° C.

Analysis: C₁₈ H₁₇ N₃ O;

Calc: C, 74.20; H, 5.88; N, 14.42;

Found: C, 74.11; H, 5.83; N, 14.17. 

What is claimed is:
 1. A method of treating inflammation in a warm-blooded mammal which comprises topically administering to such mammal an effective amount of a compound of the formula, ##STR5## wherein R is hydrogen or --(X)_(n) R₁, in which X is either O or S, n is an integer which is either 0 or 1, and R₁ is C₁ -C₈ alkyl, C₇ -C₈ aralkyl, C₃ -C₈ cycloalkyl, or C₄ -C₈ (cycloalkyl)alkyl; and R₂ and R₃ independently are halo, C₁ -C₃ alkyl, C₁ -C₃ alkoxy, or di(C₁ -C₃ alkyl)amino, with the proviso that at least one of R₂ and R₃ is halo or C₁ -C₃ alkyl; and a pharmaceutically-acceptable acid addition salt of basic members thereof.
 2. The method of claim 1, wherein R is --(X)_(n) R₁, in which R₁ is C₁ -C₈ alkyl.
 3. The method of claim 2, wherein R₁ is C₁ -C₃ alkyl.
 4. The method of claim 2, wherein the compound is 5,6-bis(4-fluorophenyl)-3-methyl-1,2,4-triazine.
 5. The method of claim 2, wherein the compound is 3-methyl-5,6-bis(4-methylphenyl)-1,2,4-triazine.
 6. The method of claim 2, wherein the compound is 5,6-bis(4-fluorophenyl)-3-methoxy-1,2,4-triazine.
 7. The method of claim 2, wherein the compound is 3-methoxy-5,6-bis(4-methylphenyl)-1,2,4-triazine.
 8. The method of claim 2, wherein the compound is 5,6-bis(4-fluorophenyl)-3-methylthio-1,2,4-triazine.
 9. The method of claim 2, wherein the compound is 5,6-bis(4-methylphenyl)-3-methylthio-1,2,4-triazine. 